Antibiotic resistance has become a major problem in hospitals and in the community and we need new antibiotics to forestall a public health crisis. The research proposed here is directed towards understanding the molecular basis by which some glycopeptide derivatives overcome antibiotic resistance and towards understanding the mechanism of action of moenomycin, a potent antibiotic that inhibits a major but underexploited antibacterial target, the transglycosyalses. Efficient chemoenzymatic and synthetic routes to glycolipid derivatives and moenomycin analogues are proposed, and the compounds that are made will be tested in both cell-based and enzymological assays in order to provide insight into structure-activity relationships. We also propose experiments to understand the mechanistic basis for how glycopeptide analogues overcome vanA and vanB resistance. A better understanding of the mechanisms by which resistance can be overcome, combined with information on how activity varies as a function of structure, could lead to the development of new antibiotics that overcome common forms of antibiotic resistance.